MiR-130b and miR-128a are essential lineage-specific co-drivers of t(4;11) MLL-AF4 acute leukemia

Malouf, C., Antunes, E. T.B., O'Dwyer, M., Jakobczyk, H., Sahm, F., Landua, S.-L., Anderson, R. A., Soufi, A., Halsey, C. and Ottersbach, K. (2021) MiR-130b and miR-128a are essential lineage-specific co-drivers of t(4;11) MLL-AF4 acute leukemia. Blood, 138(21), pp. 2066-2092. (doi: 10.1182/blood.2020006610) (PMID:34111240)

Abstract

t(4;11) MLL-AF4 acute leukemia is one of the most aggressive malignancies in the infant and pediatric population, yet we have little information on the molecular mechanisms responsible for disease progression. This impairs the development of therapeutic regimens that can address the aggressive phenotype and lineage plasticity of MLL-AF4-driven leukemogenesis. This study highlights novel mechanisms of disease development by focusing on two microRNAs upregulated in leukemic blasts from primary patient samples: miR-130b and miR-128a. We show that miR-130b and miR-128a are downstream targets of MLL-AF4 and can individually drive the transition from a pre-leukemic stage to an acute leukemia in an entirely murine Mll-AF4 in vivo model. They are also required to maintain the disease phenotype. Interestingly, miR-130b overexpression led to a mixed/B-cell precursor/myeloid leukemia, propagated by the lymphoid-primed multipotent progenitor population, whereas miR-128a overexpression resulted in a pro-B acute lymphoblastic leukemia, maintained by a highly expanded Il7r+ckit+ blast population. Molecular and phenotypic changes induced by these two miRNAs fully recapitulate the human disease, including central nervous system infiltration and activation of an MLL-AF4 expression signature. Furthermore, we identified two downstream targets of these microRNAs, NR2F6 and SGMS1, which in extensive validation studies are confirmed as novel tumour suppressors of MLL-AF4+ leukemia. Our integrative approach thus provides a platform for the identification of essential co-drivers of MLL-rearranged leukemias, in which the pre-leukemia to leukemia transition and lineage plasticity can be dissected and new therapeutic approaches can be tested.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Halsey, Professor Chris
• Authors: Malouf, C., Antunes, E. T.B., O'Dwyer, M., Jakobczyk, H., Sahm, F., Landua, S.-L., Anderson, R. A., Soufi, A., Halsey, C., and Ottersbach, K.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Blood
• Publisher: American Society of Hematology
• ISSN: 0006-4971
• ISSN (Online): 1528-0020
• Published Online: 12 June 2021
• Copyright Holders: Copyright © 2021 American Society of Hematology
• First Published: First published in Blood 138(21): 2066-2092
• Publisher Policy: Reproduced in accordance with the publisher copyright policy